title: Effect of interferon-α2b on the expression of various drug-metabolizing enzymes and transporters in co-cultures of freshly prepared human primary hepatocytes.
abstract: The purpose of this study was to assess the impact of interferon-α2b (IFN-α2b) on the expression of various drug-metabolizing enzymes and transporters in freshly prepared co-cultures (parenchymal and non-parenchymal cells) of human primary hepatocytes. At therapeutically relevant concentrations (from 1000 to 3000 IU/mL), IFN-α2b up-regulated STAT1 (signal transducer and activator of transcription factor 1) mRNA expression. Conversely, three cytochrome P450s (CYP1A2, CYP2B6, CYP2E1), a UDP-glucuronosyltransferase (UGT2B7), a sulphotransferase (SULT1A1) and organic anion transporter (OAT2) were significantly down-regulated (~50%; P < 0.05). Western blot analysis of CYP1A2, UGT2B7 and OAT2 protein supported the mRNA data. Two peroxisome proliferator activator receptor alpha (PPARα)-controlled genes (pyruvate dehydrogenase kinase 4 and adipose differentiation-related protein), CYP3A4 and multidrug resistance-associated protein 2 were significantly up-regulated (up to 223%; P < 0.05). On the other hand, SULT2A1, carboxylesterase 2, organic anion transporting peptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1, P-glycoprotein and breast cancer resistance protein mRNA expression was not significantly affected. Western blot analysis of CYP3A4 supported the mRNA data also. The present results demonstrated complex interactions between IFN-α2b and hepatocytes and the observed down-regulation of CYP1A2, OAT2 and UGT2B7 is consistent with reports of drug interactions between IFN-α2b and drugs such as theophylline, clozapine and gemfibrozil.
authors.affiliation: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ 08543, USA. cliff.chen@bms.com
authors.forename: Cliff
authors.initials: C
authors.lastname: Chen
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D000070780:Perilipin-2; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008565:Membrane Proteins; D029362:Organic Anion Transporters, Sodium-Independent; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; C490280:SLC22A7 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585599:CYP2B6 protein, human; C110332:CYP2F1 protein, human; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D015238:Sulfotransferases; D002265:Carboxylic Ester Hydrolases